Drug delivery systems and methods for treatment of bladder cancer

ABSTRACT

Methods, devices, and medicaments that include oxaliplatin are provided for use in the treatment of bladder cancer by locally administering oxaliplatin into the bladder of a patient to achieve a sustained concentration of oxaliplatin in urine in the bladder sufficient to produce a therapeutic concentration of oxaliplatin in bladder tissue. The oxaliplatin may be delivered into the bladder from an intravesical drug delivery device inserted into the bladder, wherein the device continuously releases the oxaliplatin into the urine in the bladder over an extended period of hours or days.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of PCT/US2013/057836, filed 3 Sep.2013, which claims priority to U.S. Provisional Patent Application No.61/696,027, filed Aug. 31, 2012, which are incorporated herein byreference.

BACKGROUND

This disclosure is generally in the field of pharmaceutical agents foruse in treating the bladder, and more particularly to drug deliverysystems, methods, and drug formulations for targeted treatment ofurinary bladder cancer.

Delivery of therapeutic agents to the urinary bladder is difficult.Current practice requires systemic administration using doses whichresult in significant exposure to healthy tissues and relatively lowexposure within the bladder. Frequently the systemic exposure leads tounwanted or harmful side effects which limit the usefulness of the agentin treating bladder disease.

To avoid systemic effects, drugs may be delivered locally onto tissuesat or near the target tissue. However, such local administration may notbe well tolerated by the tissue at the delivery site and/or may not besufficiently permeable to the particular drug being delivered.Accordingly, there is a need to provide a therapeutic agent that is welltolerated by the bladder when the agent is applied at concentrationseffective to achieve sufficient therapeutic (i.e., cytotoxic)concentrations within the target tissues.

Accordingly, there remains a need for improved drug delivery methods andsystems for treating the bladder, such as in the treatment of bladdercancer, whether as neoadjuvant therapy, adjuvant therapy, or palliativetherapy.

SUMMARY

In one aspect, a medicament is provided that includes oxaliplatin foruse in the treatment of bladder cancer by locally administeringoxaliplatin into the bladder of a patient to achieve a sustainedconcentration of oxaliplatin in urine in the bladder sufficient toproduce a therapeutic concentration of oxaliplatin in bladder tissue.The locally administering into the patient's bladder may be continuousor intermittent. In one embodiment, the oxaliplatin is delivered intothe bladder from an intravesical drug delivery device inserted into thebladder, and the device continuously releases the oxaliplatin into theurine in the bladder over a sustained period. In an alternativeembodiment, the oxaliplatin is delivered into the bladder from a coatingsubstance applied to the bladder, which coating substance continuouslyreleases the oxaliplatin into the urine in the bladder over a sustainedperiod. The coating substance may include a mucoadhesive formulation. Ina further alternative embodiment, a liquid form of the oxaliplatin ispumped into the bladder through a urethral catheter inserted into thebladder. In various embodiments, the oxaliplatin is released into thepatient's bladder continuously over a period of at least 2 hours, suchas from 1 day to 14 days. In an embodiment, the oxaliplatin is releasedinto the patient's bladder at a mean average amount of from 1 mg toabout 100 mg oxaliplatin per day for 1 day to 14 days. In an embodiment,the oxaliplatin is released into the patient's bladder at a mean averageamount of from 1 mg to about 100 mg oxaliplatin per day for up to 7days.

In another aspect, a medical device is provided for intravesicaladministration of oxaliplatin. In an embodiment, the device includes ahousing configured for intravesical insertion, and a dosage formcomprising oxaliplatin, wherein the housing holds the dosage form and isconfigured to controllably release the oxaliplatin into the bladder inamount therapeutically effective for the treatment of bladder cancer. Inan embodiment, the device comprises is elastically deformable between aretention shape configured to retain the device in a patient's bladderand a deployment shape for passage of the device through the patient'surethra. In an embodiment, the device is configured to release from 1mg/day to 100 mg/day of oxaliplatin for up to 7 days.

In still another aspect, a method is provided for administeringoxaliplatin to a patient in need of treatment of bladder cancer. Themethod includes locally administering oxaliplatin into the bladder of apatient to achieve a sustained concentration of oxaliplatin in urine inthe bladder sufficient to produce a therapeutic concentration ofoxaliplatin in bladder tissue. The method may further includeadministering at least a second therapeutic agent to the patient.Non-limiting examples of second therapeutic agents include gemcitabineor another cytotoxic agent; an analgesic agent; an anti-inflammatoryagent; or a combination thereof. The second therapeutic agent may beadministered intravesically and/or by other routes of administration.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1B illustrate one embodiment of an intravesical drug deliverydevice that may be used for administering oxaliplatin as describedherein. FIGS. 2A-2B illustrate another embodiment of an intravesicaldrug delivery device that may be used for administering oxaliplatin asdescribed herein.

FIGS. 3A-3C illustrate still another embodiment of an intravesical drugdelivery device that may be used for administering oxaliplatin asdescribed herein.

FIGS. 4A-4B illustrate a method of inserting an intravesical drugdelivery device into the bladder of a patient for local administrationof oxaliplatin as described herein.

FIG. 5A illustrates a material applied to the inner surface of thebladder wall for local administration of oxaliplatin as describedherein.

FIG. 5B illustrates a method of applying a coating material onto to theinner surface of the bladder wall for local administration ofoxaliplatin as described herein.

FIG. 6 is a graph of cisplatin blood profile from a study administeringthe drug by IV bolus or intra-bladder perfusion in rats.

FIGS. 7A-7C are graphs of cisplatin terminal concentrations in blood,urine, and tissue samples from a study in rats.

FIG. 8 is a graph of carboplatin blood profile from a studyadministering the drug by IV bolus or intra-bladder perfusion in rats.

FIG. 9 is a graph of carboplatin terminal concentrations in blood,urine, and tissue samples from a study in rats.

FIG. 10 is a graph showing cisplatin, carboplatin, and oxaliplatin bloodlevels following 72 hour bladder perfusion in rat study.

FIG. 11 is a graph showing oxaliplatin terminal concentrations intissues following 72 hour bladder perfusion in rat study

FIGS. 12A-12B are graphs showing cisplatin, carboplatin, and oxaliplatinbladder permeability following 72 hour bladder perfusion in rat study.

DETAILED DESCRIPTION

It has been discovered that intravesical administration of oxaliplatincan be used to achieve therapeutically effective amount of the drug inthe tissues where needed and also is well tolerated by the bladdertissue. That is, oxaliplatin was unexpectedly shown to meet both thetissue permeability criteria and the urothelium tolerability criteriawhen administered into the bladder. Several other drugs tested failed toachieve both. Furthermore, by local, intravesical administration of theoxaliplatin, systemic exposure to the drug is advantageously minimized.

Accordingly, the present methods and devices for treating bladder cancerinclude locally administering oxaliplatin into the bladder of a patientto achieve a sustained concentration of oxaliplatin in urine in thebladder sufficient to produce a therapeutic concentration of oxaliplatinin bladder tissue.

As used herein, the term “bladder tissue” refers to the bladder wall orone or more layers thereof (e.g., mucosa, muscle, and submucosa).

The term “patient” as used herein refers to humans or other mammals,such as in veterinary or livestock applications, in need of treatment.In a particular embodiment, the patient is an adult human.

Oxaliplatin is platinum-based antineoplastic agent. It is known for usein chemotherapy, for example in the treatment of colorectal cancer,where it is formulated for intravenous administration, e.g., Eloxatin™(Sanofi-Aventis). In the present invention, the oxaliplatin isformulated for local delivery. It may be provided in solid or semi-solidform or in a liquid form, depending on the delivery mechanism employed,as described herein. Oxaliplatin and methods of manufacture thereof aredescribed, for example, in U.S. Pat. Nos. 5,338,874; 5,420,319;5,716,988; and 5,290,961.

A variety of methods can be used to achieve the required urine (and thustissue) concentrations of the oxaliplatin. In one embodiment, theoxaliplatin can be provided by direct instillation of a simple solutioninto the bladder. For example, a solution of the oxaliplatin may bepumped into the bladder through a urethral or suprapubic catheter in acontinuous or pulsatile manner over the treatment period. In anotherembodiment, the oxaliplatin is released from a device or compositiondeployed in the bladder, wherein the device or composition releases theoxaliplatin (continuously or intermittently) at a rate effective toproduce the desired concentration of drug in the urine over a specifiedtreatment period. At the end of the treatment period, the device may beretrieved from the bladder, or it may be eliminated by being resorbed,dissolved, excreted, or a combination thereof.

In a preferred embodiment, the oxaliplatin is administered to thebladder from an intravesical device. A preferred embodiment of anintravesical drug delivery device and methods for deploying thosedevices into the bladder are described in the following U.S. PatentApplication Publications: US 2012/0203203 (Lee et al.); US 2012/0089122(Lee et al.); US 2012/0089121 (Lee et al.); US 2011/0218488 (Boyko etal.); US 2011/0202036 (Boyko et al.); US 2011/0152839 (Cima et al.); US2011/0060309 (Lee et al.); US 2010/0331770 (Lee et al.); US 2010/0330149(Daniel et al.); US 2010/0003297 (Tobias et al.); US 2009/0149833 (Cimaet al.); and US 2007/0202151 (Lee et al.).

In embodiments in which the oxaliplatin is delivered from anintravesical drug delivery device, the oxaliplatin may be housed in thedevice in various forms, which may depend on the particular mechanism bywhich the device controllably releases the oxaliplatin into fluid (e.g.,urine) in the bladder. In some embodiments, the oxaliplatin is providedin a solid, semi-solid, or other non-liquid form, which advantageouslymay facilitate stable storage of the drug before the device is used andadvantageously may enable the drug payload of the device to be stored insmaller volume than would be possible if the drug were housed in theform of a liquid solution. In an embodiment the non-liquid form isselected from tablets, granules, semisolids, capsules, and combinationsthereof. In one embodiment, the oxaliplatin is in the form of aplurality of tablets, such as mini-tablets described in U.S. Pat. No.8,343,516, which is incorporated herein in pertinent part. In otherembodiments, the oxaliplatin may be housed in a liquid form, such as ina solution with a pharmaceutically acceptable excipient.

An embodiment of a drug delivery device 100 is illustrated in FIG. 1A.The device 100 includes a device body having a drug reservoir portion102 and a retention frame portion 104. In FIG. 1, the device 100 isshown in a relatively expanded shape suited for retention in the body.Following deployment into the body, the device 100 may assume therelatively expanded shape to retain the drug delivery device in the bodycavity or lumen.

For the purposes of this disclosure, terms such as “relatively expandedshape”, “relatively higher-profile shape”, or “retention shape”generally denote any shape suited for retaining the device in theintended implantation location, including but not limited to the pretzelshape shown in FIG. 1 that is suited for retaining the device in thebladder. Similarly, terms such as “relatively lower-profile shape” or“deployment shape” generally denote any shape suited for deploying thedrug delivery device into the body, including a linear or elongatedshape that is suited for deploying the device through the workingchannel of catheter, cystoscope, or other deployment instrumentpositioned in the urethra. In embodiments, the drug delivery device maynaturally assume the relatively expanded shape and may be deformed,either manually or with the aid of an external apparatus, into therelatively lower-profile shape for insertion into the body. Oncedeployed the device may spontaneously or naturally return to theinitial, relatively expanded shape for retention in the body.

In the illustrated embodiment, the drug reservoir and retention frameportions 102, 104 of the drug delivery device 100 are longitudinallyaligned and are coupled to each other along their length, although otherconfigurations are possible. The drug delivery device 100 includes anelastic or flexible device body 106 that defines a drug reservoir lumen108 (i.e., the drug housing) and a retention frame lumen 110. The drugreservoir lumen 108 is designed to house a drug formulation thatcomprises the oxaliplatin. In the illustrated embodiment, the drugformulation in the form of a number of solid drug tablets 112. Theretention frame lumen 110 is designed to house a retention frame 114 toform the retention frame portion 104. The illustrated lumens 108, 110are discrete from each other, although other configurations arepossible.

As shown in the cross-sectional view of FIG. 1B, the device body 106includes a tube or wall 122 that defines the drug reservoir lumen 108and a tube or wall 124 that defines the retention frame lumen 110. Thetubes 122, 124 and lumens 108, 110 can be substantially cylindrical,with the drug reservoir lumen 108 having a relatively larger diameterthan the retention frame lumen 110, although other configurations can beselected based on, for example, the amount of drug to be delivered, thediameter of the retention frame, and deployment considerations such asthe inner diameter of the deployment instrument. The wall 124 thatdefines the retention frame lumen 110 may extend along the entire lengthof the wall 122 that defines the drug reservoir lumen 108, so that theretention frame lumen 110 has the same length as the drug reservoirlumen 108 as shown, although one wall may be shorter than the other wallin other embodiments. The two walls 122, 124 are attached along theentire length of the device in the illustrated embodiment, althoughintermittent attachment can be employed.

As shown in FIG. 1A, the drug reservoir lumen 108 is loaded with anumber of drug units 112 in a serial arrangement. Essentially any numberof drug units may be used, for example, depending upon the sizes of thereservoir and the drug units. The drug reservoir lumen 108 includes afirst end opening 130 and an opposed second end opening 132. Once thedrug units 112 are loaded, restraining plugs 120 are disposed in theopenings 130 and 132. The restraining plugs 120, in this embodiment, arecylindrical plugs secured into the entry 130 and the exit 132. In otherembodiments, the openings 130 and 132 are closed off with otherstructures or materials, which may, depending on the particularembodiments, include an aperture or a water- or drug-permeable wall tofacilitate ingress or egress of water or drug during use.

The retention frame lumen 110 is loaded with the retention frame 114,which may be an elastic wire. The retention frame 110 may be configuredto return spontaneously to a retention shape, such as the illustratedexample “pretzel” shape or another coiled shape, such as those disclosedin the applications previously incorporated. In particular, theretention frame 114 may retain the device 100 in the body, such as inthe bladder. For example, the retention frame 114 may have an elasticlimit and modulus that allows the device 100 to be introduced into thebody in a relatively lower-profile shape, permits the device 100 toreturn to the relatively expanded shape once inside the body, andimpedes the device from assuming the relatively lower-profile shapewithin the body in response to expected forces, such as the hydrodynamicforces associated with contraction of the detrusor muscle and urination.Thus, the device 100 may be retained in the body once implanted,limiting or prevent accidental expulsion.

The material used to form the device body 106, at least in part, may beelastic or flexible to permit moving the device 100 between deploymentand retention shapes. When the device is in the retention shape, theretention frame portion 104 may tend to lie inside the drug reservoirportion 102 as shown, although the retention frame portion 104 can bepositioned inside, outside, above, or below the drug reservoir portion102 in other cases.

The material used to form the device body 106 may be water permeable sothat solubilizing fluid (e.g., urine or other bodily fluid) can enterthe drug reservoir portion 102 to solubilize the drug units 112 once thedevice is implanted. For example, silicone or another biocompatibleelastomeric material may be used. In other embodiments, the device bodymay be formed, at least in part, of a water-impermeable material.

FIG. 2A illustrates an implantable drug delivery device 200, whichincludes a drug reservoir 202 loaded with drug 212 and a retentionstructure that includes two filaments 220, 222 associated with afastener 230. As shown, the drug reservoir 202 is an elongated tube thatcan be deformed between a relatively linear deployment shape, such asthe shape shown in FIG. 2A, and a relatively circular retention shape,such as the shape shown in FIG. 2B. The drug 212 may be loaded in thetube in a flexible form, so that the drug reservoir 102 can be movedbetween the two shapes. For example, the drug 212 may be a number ofsolid drug tablets, a liquid, or a gel. The filaments 220, 222 may beattached to opposite ends of the drug reservoir 202 and joined by thefastener 230. The fastener 230 can be adjusted to adjust the position ofone filament 220 with reference to the other 222, thereby adjusting theposition of one end of the drug reservoir 2102 with reference to theother end. The device 200 can assume the retention shape by adjustingthe filaments 220, 222 to draw the ends of the drug reservoir 202 closertogether, and thereafter the device 200 can be retained in the retentionshape by preventing adjustment of the filaments 220, 222 with thefastener 230. In such an embodiment, the device 200 is manually adjustedinto the retention shape by manually adjusting the filaments 220, 222after the device 200 is inserted into the bladder.

In the illustrated embodiment, the fastener 230 is a cinch nut thatpermits shortening the portion of the filaments 220, 222 between thedrug reservoir ends and the cinch nut, but prevents lengthening of theseportions of the filaments 220, 222. Thus, the ends of the drug reservoir202 can be drawn closer together by pulling one or both of the filaments220, 222 through the cinch nut, causing the device 200 to assume theretention shape. Once the filaments 220, 222 have been so adjusted, thecinch nut prevents lengthening of the filaments 220, 222, retaining thedevice in the retention shape. Thus, manually adjusting the device 200into the retention shape once implanted merely requires pulling one orboth of the filaments 220, 222, although other fasteners 230 thatrequire separate manipulation can be employed. Other fasteners may alsobe used.

Another embodiment of an intravesical drug delivery device isillustrated in FIGS. 3A-3C. In this embodiment, the device includes ahousing 300 having a single, continuous structure with multiple,discrete drug reservoir lumens 320 and optionally having at least oneretention frame lumen 330 in which a retention frame 360 is disposed.Each drug reservoir lumen 320 has two defined openings, as shown in FIG.3B, and is dimensioned to hold at least one solid drug unit 340. Soliddrug unit 340 may be a drug tablet or capsule. In other embodiments notshown, each drug reservoir lumen has one defined opening. The housingmay be formed of a flexible polymer, such as silicone. FIG. 3B is across-sectional view of the plane that bisects one of the drug reservoirlumens 320 of the housing shown in FIG. 3A along line 3B-3B. As shown inFIG. 3B, the monolithic housing 300 has two defined openings (350 a, 350b) in its drug reservoir lumen 320 that expose both ends of the soliddrug unit 340. The retention frame lumen 330, in this embodiment, isaligned parallel to the longitudinal axis of the housing andperpendicular to the drug reservoir lumen 320.

FIG. 3C is a perspective view of a portion of the embodiment of thedevice 300 shown in FIG. 3A when the device is in its retention shape,which is taken when the retention frame 360 is disposed in the retentionframe lumen 330. The drug reservoir lumens 320 and the retention frame360 in the housing of this embodiment are oriented so that the drugreservoir lumens 320 are outside the retention frame's 360 arc.Alternatively, the housing in FIG. 3C can be rotated 180 degrees aboutthe retention frame 360 to yield a configuration in which the drugreservoir lumens 320 are arranged within the retention frame's 360 arc.With this embodiment, the devices provide sufficient direct contactbetween solid drug units and with urine surrounding the device whendeployed and retained in the bladder. In embodiments, release of thedrug from the device is controlled by erosion of an exposed portion ofthe surface of a solid drug unit, such that the rate of drug releasefrom the drug delivery device may be directly proportional to andlimited by the total exposed surface area of the solid drug units.

One embodiment of inserting an intravesical device 400 for subsequentcontrolled release of the oxaliplatin into the bladder is shown in FIGS.4A and 4B. Here, the device 400 is shown assuming a retention shape asthe device exits a deployment instrument 402. The deployment instrument402 may be any suitable device. It may be a lumenal device, such as acatheter, urethral catheter, or cystoscope. The deployment instrument402 may be a commercially available device or a device specially adaptedfor the present drug delivery devices. FIG. 4B illustrates the insertionof the device 400 into the bladder, wherein the adult male anatomy isshown by way of example. The deployment instrument 402 is insertedthrough the urethra to the bladder, and the device 400 may be passedfrom/through the deployment instrument 402, driven by a stylet or flowof lubricant or combination thereof until the device 400 exits into thebladder, and as shown is in a retention shape.

In various embodiments, the oxaliplatin may be released from theintravesical drug delivery device by diffusion to through a wall of thedrug housing, by diffusion to through one or more defined apertures in awall of the drug housing, by osmotic pressure through an aperture in thedrug housing, by erosion of a drug formulation in contact with urine inthe bladder, or by a combination thereof.

In some embodiments in which the device comprises a drug in a solidform, elution of drug from the device occurs following dissolution ofthe drug within the device. Bodily fluid enters the device, contacts thedrug and solubilizes the drug, and thereafter the dissolved drugdiffuses from the device or flows from the device under osmotic pressureor via diffusion. For example, the drug may be solubilized upon contactwith urine in cases in which the device is implanted in the bladder.

In various embodiments, the intravesical device may release oxaliplatincontinuously or intermittent to achieve a therapeutically effectiveconcentration of oxaliplatin in the bladder tissue over a sustainedperiod, e.g., from 1 hour to 1 month, for example from 2 hours to 2weeks, from 6 hours to 1 week, from 24 hours to 72 hours, etc.

Subsequently, the device may be retrieved from the body, such as incases in which the device is non-resorbable or otherwise needs to beremoved. Retrieval devices for this purpose are known in the art or canbe specially produced. The device also may be completely or partiallybioresorbable, such that retrieval is unnecessary, as either the entiredevice is resorbed or the device sufficiently degrades for expulsionfrom the bladder during urination. The device may not be retrieved orresorbed until some of the drug, or preferably most or all of the drug,has been released. If needed, a new drug-loaded device may subsequentlybe implanted, during the same procedure as the retrieval or at a latertime.

In another embodiment, a coating substance may be intravesically appliedto the bladder wall, wherein the coating substance includes oxaliplatinand one or more excipient materials that promote adherance of thecoating substance to the bladder wall and provides continuous controlledrelease of the drug over the treatment period. The coating substance maybe a mucoadhesive formulation, such as gels, ointments, creams, films,emulsion gels, tablets, polymers, or a combination thereof. Mucoadhesiveformulation polymers may include hydrogels or hydrophilic polymers,polycarbophil (i.e. Carbopols, etc.), chitosan, polyvinylpyrrolidone(PVP), lectin, polyethyleneglycolated polymers, celluloses, or acombination thereof. Suitable celluloses include methyl cellulose (MC),carboxymethyl cellulose (CMC), hydroxypropyl cellulose (HPC), orcombinations thereof. The coating substance may include a permeationenhancer. Non-limiting examples of permeation enhancers include dimethylsulfoxide (DMSO), sodium carboxymethyl cellulose (NaCMC), lipids,surfactants, or combinations thereof.

As shown in FIG. 5A, a coating substance 500 may be deployed in thebladder 550 so that the coating substance 500 engages/adheres to thebladder wall 552. The coating substance 500 may be deployed in thebladder using a deployment instrument. FIG. 5B is a sagittal view of amale genitourinary system, illustrating a coating substance 500 beingdeployed through a deployment instrument 502 into the bladder 550. Thecoating substance 500 may be an embodiment of one of the coatingsubstances described herein. The deployment instrument 502 is sized andshaped for passing through a urethra 560 of a patient to a bladder 550as shown. The deployment instrument 502 may be a known device, such as acatheter or cystoscope, or a specially designed device. The deploymentinstrument 502 is used to deploy the coating substance 500 into thebladder and is subsequently removed from the body, leaving the coatingsubstance 500 in the bladder. Once so inserted, the coating substance500 releases the oxaliplatin into urine and the bladder wall. Thepresent invention may be further understood with reference to thefollowing non-limiting examples.

EXAMPLE 1 Testing of Platin Drugs for Bladder Tolerability and TissuePermeability

Two studies were conducted in male Sprague Dawley rats administeringcisplatin or carboplatin by intra-urinary bladder cannula, over a72-hour continuous perfusion, or by a single IV bolus. Blood, urine, andtissue samples were collected and analyzed for drug content. Details ofthe study design and results are set forth in the tables and descriptionbelow.

The study protocol was as follows:

Cisplatin Carboplatin Group 1 24-hr perfusion via cannula 24-hrperfusion via cannula to to bladder dome bladder dome Group 2 72-hrperfusion via cannula 72-hr perfusion via cannula to to bladder domebladder dome Group 3 Negative control - 72-hr Negative control - 72-hrperfusion via cannual to perfusion via cannual to bladder dome bladderdome Group 4 IV bolus with saline IV bolus with saline perfusionperfusion via cannula via cannula

For each drug, each test group included three male rats. The perfusatedrug concentration was set to 0.3 mg/mL and the perfusion rate used was300 μL/hour over the test periods.

Details of the study design and results are set forth in the tables anddescriptions below.

Perfusion solutions were prepared by dissolving each drug substance intoan appropriate volume of saline. The finals doses administered aresummarized below.

Amount Compound Admin- Actual Dose istered Admin- Administration viaPerfusion istered Animal # Compound Route Wt. (g) (mg/kg)  1 (Group 1)Cisplatin Bladder Perf. 6.95 2.14  2 (Group 1) Cisplatin Bladder Perf.6.88 2.12  3 (Group 1) Cisplatin Bladder Perf. 7.02 2.16  4 (Group 2)Cisplatin Bladder Perf. 20.44 6.30  5 (Group 2) Cisplatin Bladder Perf.21.20 6.53  6 (Group 2) Cisplatin Bladder Perf. 20.59 6.34 10 (Group 4)Cisplatin IV Bolus 0.9820 0.74 11 (Group 4) Cisplatin IV Bolus 1.03190.77 12 (Group 4) Cisplatin IV Bolus 1.1210 0.84 22 (Group 1)Carboplatin Bladder Perf. 7.08 2.18 23 (Group 1) Carboplatin BladderPerf. 6.87 2.12 24 (Group 1) Carboplatin Bladder Perf. 7.02 2.16 25(Group 2) Carboplatin Bladder Perf. 20.89 6.43 26 (Group 2) CarboplatinBladder Perf. 21.22 6.54 27 (Group 2) Carboplatin Bladder Perf. 20.706.38 31 (Group 4) Carboplatin IV Bolus 1.1155 0.84 32 (Group 4)Carboplatin IV Bolus 1.1507 0.86 33 (Group 4) Carboplatin IV Bolus1.1195 0.84Whole blood samples were collected at various time points following thestart of perfusion, including times 0, 12, 24, 48 and 72 hours asapplicable. Urine was collected pre-dose and for 0-24, 24-48, and48-72-hour periods post dose.

Following the planned infusion periods the animals, terminal bloodsamples were taken via the abdominal aorta, and the bladder, prostate,ureter, and kidney tissues were collected, weighed, and visuallyinspected for evidence of drug tolerability.

For animals dosed with cisplatin (Groups 1, 2, and 4), all animalsappeared normal during perfusion period except as noted below. Tissueobservations at necropsy are also summarized.

Clinical Observations Group of note during Numbers Perfusion TissueObservations at Necropsy Group 1 Normal Bladder lumen: slight to milderythemic (Animals discoloration, 30-50% of lumen, mild to 1, 2, 3)moderate severity, mild edema/thickened bladder walls Group 2 Red tintedBladder lumen: generalized erythemic (Animals urine at 72 discoloration,30-50% of lumen, mild to 4, 5, 6) hrs, all animals moderate severity,blood clots, moderate edema/thickened bladder walls Group 3- Darkcolored Slight to mild focal erythemia CONTROL urine (one (Animalsanimal @ 7, 8, 9) 46 hr) Group 4 Normal No observations (Animals 10, 11,12)

For animals dosed with carboplatin, all animals appeared normal duringperfusion period. Tissue observations at necropsy are also summarized.

Clinical Observations of note Group during Numbers Perfusion TissueObservations at Necropsy Group 1 Normal Bladder lumen: slight to mildgeneralized (Animals erythemic discoloration, 10-30% of lumen, 22, 23,24) no evidence of tissue edema Group 2 Normal Bladder lumen: slight tomild generalized (Animals erythemic discoloration, 10-30% of lumen, 25,26, 27) no evidence of tissue edema Group 3- Red tinted Bladder lumen:slight generalized erythemic CONTROL urine (one discoloration, 5-10% oflumen, mild tissue (Animals animal) edema (one animal) 28, 29, 30) Group4 Red tinted Bladder lumen: slight generalized erythemic (Animals urine(one discoloration, 5-10% of lumen, no evidence 31, 32, 33) animal) oftissue edema

Gross pathology observations were substantiated by tissue histology.ICP-MS for platinum was used to test (i) serial whole blood, (ii) dailyurines in 24-hr collections, and (iii) terminal tissues, includingbladder, kidney, and prostate. FIG. 6 is a graph showing the bloodprofile for cisplatin. The 72 h group show rising blood levelssuggesting degradation of the bladder lumen permitting increased tissuecisplatin uptake. FIGS. 7A and 7B are graphs showing cisplatin terminalconcentrations in the various tissue and fluid samples. Significantlyhigher and more variable bladder platinum concentrations were observedfollowing 72 hr perfusions when compared to 24 hr perfusions and wereassociated with the pronounced bladder tissue toxicities observed atnecropsy. Individual 72 hr bladder concentration values were 12,000ng/g, 60,000 ng/g and 160,000 ng/g.

IV bolus administration resulted in measurable kidney and bladder tissueplatinum levels at 72 hrs despite low urine concentrations. In the IVdosing group kidney to bladder platinum concentration ratio was theinverse of that observed following bladder perfusion. Kidney tissueconcentration was highest, followed by the bladder concentration both ofwhich were achieved at approximately half the plasma concentrationsobserved at 72 h. Increased bladder concentration observed followingperfusion may reflect absorption by bladder from both systemic (blood)and urine (urinary clearance) of platinum (which is also supported byelevated kidney levels).

FIG. 7C is another graph showing cisplatin terminal concentrations. Thebladder:urine ratio was near 100% for the 72 h perfusion (tox). Thebladder:urine ratio was 5% for the 24 h perfusion, which reflectscisplatnin partitioning when the urothelium is less damaged, exhibitingonly mild to moderate erythema as observed in the 24 hr necropsy results(Group 1). For whole blood, the bladder ratio was 66% at 72 hr for theIV bolus administration due to the long half-life of platinum compoundswhen administered systemically. These results confirm a significantadvantage of intravescular bladder perfusion when the urothelium islargely intact. Significant bladder levels can be attained withoutmeaningful systemic exposure.

FIG. 8 is a graph showing the blood profile for carboplatin. Observedplasma levels were near the limit of the assay detection (twice thelimits of detection) to below the quantitation limit were observed forthe perfusion groups. The IV bolus shows significant peak systemicplatinum exposure followed by a sharp decay (faster clearance thanobserved with cisplatin). There was one quarter less carboplatin in theIV bolus terminal phase as compared with cisplatin.

FIG. 9 is a graph showing carboplatin terminal concentrations in thevarious tissue and fluid samples. Note the scale difference compared toFIG. 6. Carboplatin tissue levels were observed to be consistently lessthan those observed following cisplatin bladder perfusion. In thebladder, tissue concentrations were below the IC₅₀ of carboplatin. Thefindings suggest intravesical perfusion of carboplatin does not achievetherapeutic tissue platinum concentrations.

EXAMPLE 2 Oxaliplatin Screening for Bladder Tolerability and TissuePermeability

A study was conducted in male Sprague Dawley rats administeringoxaliplatin, oxybutynin, trospium, or tolterodine by intra-urinarybladder cannula, over a 72-hour continuous perfusion. Blood, urine, andtissue samples were collected and analyzed for drug content. Details ofthe study design and results are set forth in the tables anddescriptions below.

Actual Dose Amount Administered Compound per animal Admin- Administeredbased on istration via Syringe syringe Animal # Compound Route Wt. (g)Wt. (mg/kg) 47 Oxaliplatin Bladder Perf. 21.28 6.55 48 OxaliplatinBladder Perf. 21.06 6.49 49 Oxaliplatin Bladder Perf. 22.29 6.37Clear solutions of oxaliplatin were prepared in saline vehicle. Theperfusate formulation concentration was 0.308 mg/mL. Dose (mg/kg) wascalculated as (Dose administered (g) x formulation concentration(mg/mL))/Animal Wt. (kg). The drug solutions were dosed over a 72-hourperiod into the non-fasted animal's bladder by intra-urinary bladdercannula using an infusion pump. This dose was selected based resultsobserved with carboplatin and cisplatin.

Whole blood samples were taken via tailnick or jugular vein cannula atthe following time points following the start of perfusion: 0, 4, 8, 24,and 48 hours. Urine was collected pre-dose and for 0-24, 24-48, and48-72-hour periods post dose. All animals appeared normal throughout thestudy.

Following the 72-hour infusion period the animals were sacrificed,terminal blood samples were taken via the abdominal aorta, and bladder,prostate, ureter, and kidney tissues were collected, weighed, andvisually inspected for evidence of tolerability/reaction from exposureto the drug. All tissues appeared normal except as noted below:

Animal # Observations 47 Slight erythemia 20% of surface, on inside wallof bladder associated with the bladder cannula mild erythemia noted 48Slight erythemia 20% of surface, on inside wall of bladder associatedwith the bladder cannula moderate erythemia and edema noted 49 Slighterythemic <5% of surface, otherwise normal urothelium

FIG. 10 compares the blood profiles for cisplatin, carboplatin, andoxaliplatin. Comparing these graphs, it was observed that oxaliplatinconcentrations fell between cisplatin and carboplatin.

FIG. 11 graphs of the terminal bladder concentrations for oxaliplatin.Oxaliplatin data showed a bladder:urine ratio of 10%. No appreciableplatinum concentration was observed in the kidney or prostate.

FIGS. 12A and 12B compare bladder platinum concentrations followingcisplatin, carboplatin and oxaliplatin bladder perfusion. Surprisingly,oxaliplatin exhibited significant platinum bladder concentrationscompared to the trends observed following cisplatin and carboplatin.Comparatively low blood and kidney platinum concentrations were observedin contrast to cisplatin. In comparison to carboplatin, high bladderplatinum concentrations were associated with comparably low platinumlevels in the blood.

The results surprisingly show both bladder tolerability and tissuepermeability for oxaliplatin, but that cisplatin and carboplatin meetonly one or other of these criteria (see Example 1).

Publications cited herein and the materials for which they are cited arespecifically incorporated by reference. Modifications and variations ofthe methods and devices described herein will be obvious to thoseskilled in the art from the foregoing detailed description. Suchmodifications and variations are intended to come within the scope ofthe appended claims.

I claim:
 1. A method of treatment of bladder cancer comprising: locallyadministering oxaliplatin into the bladder of a patient to achieve asustained concentration of oxaliplatin in urine in the bladdersufficient to produce a therapeutic concentration of oxaliplatin inbladder tissue wherein the locally administering is continuous over aperiod of at least one day.
 2. The method of claim 1, wherein thelocally administering into the patient's bladder is at a mean averageamount of from 1 mg to about 100 mg oxaliplatin per day for 1 day to 14days.
 3. The method of claim 1, wherein the locally administering intothe patient's bladder is at a mean average amount of from 1 mg to about100 mg oxaliplatin per day for up to 7 days.
 4. The method of claim 1,wherein the oxaliplatin is delivered into the bladder from anintravesical drug delivery device which continuously releases theoxaliplatin into the urine in the bladder over a sustained period. 5.The method of claim 4, wherein the intravesical drug delivery devicecontinuously releases the oxaliplatin into the urine in the bladder overa period of 1 day to 14 days.
 6. The method of claim 4, wherein theintravesical drug delivery device comprises a housing which contains andcontrollably releases the oxaliplatin and which is elasticallydeformable between a retention shape configured to retain the device ina patient's bladder and a deployment shape for passage of the devicethrough the patient's urethra.
 7. The method of claim 6, wherein theoxaliplatin contained in the housing is in a non-liquid form.
 8. Themethod of claim 7, wherein the non-liquid form is selected from thegroup consisting of tablets, granules, semisolids, capsules, andcombinations thereof.
 9. The method of claim 1, further comprisingadministering at least a second therapeutic agent to the patient. 10.The method of claim 9, wherein the second therapeutic agent isadministered intravesically.
 11. The method of claim 9, wherein thesecond therapeutic agent comprises gemcitabine or another cytotoxicagent; an analgesic agent; an anti-inflammatory agent; or a combinationthereof.
 12. The method of claim 1, wherein the locally administeringinto the patient's bladder is continuous over a 72-hour period at a meanaverage amount of from about 6.3 to about 6.5 mg/kg over the period. 13.A method of administering oxaliplatin to a patient in need of treatmentof bladder cancer, the method comprising: locally administeringoxaliplatin into the bladder of a patient to achieve a sustainedconcentration of oxaliplatin in urine in the bladder sufficient toproduce a therapeutic concentration of oxaliplatin in bladder tissue,wherein the oxaliplatin is administered into the bladder from anintravesical drug delivery device which continuously releases theoxaliplatin into the urine in the bladder over a sustained period of atleast one day.
 14. The method of claim 13, wherein the intravesical drugdelivery device continuously releases the oxaliplatin into the urine inthe bladder at a mean average amount of between 1 mg and 100 mgoxaliplatin per day.
 15. The method of claim 13, wherein theintravesical drug delivery device continuously releases the oxaliplatininto the urine in the bladder over a period of 1 day to 14 days.
 16. Amethod of administering oxaliplatin to a patient in need of treatment ofbladder cancer, the method comprising: locally continuouslyadministering oxaliplatin into the bladder of a patient to achieve asustained concentration of oxaliplatin in urine in the bladdersufficient to produce a therapeutic concentration of oxaliplatin inbladder tissue, wherein the oxaliplatin is administered into the bladderfrom an intravesical drug delivery device which continuously releasesthe oxaliplatin into the urine in the bladder over a period from 7 daysto 14 days.
 17. The method of claim 16, wherein the oxaliplatin isreleased at a mean average amount of from 1 mg to 100 mg per day overthe period.